Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology

Alzheimer's disease has long been known to involve cholinergic deficits, but the linkage between cholinergic gene expression and the Alzheimer's disease amyloid pathology has remained incompletely understood. One known link involves synaptic acetylcholinesterase (AChE-S), shown to accelerate amyloid fibrils formation. Here, we report that the ‘Readthrough' AChE-R splice variant, which differs from AChE-S in its 26 C-terminal residues, inversely exerts neuroprotective effects from amyloid β (Aβ) induced toxicity. In vitro, highly purified AChE-R dose-dependently suppressed the formation of insoluble Aβ oligomers and fibrils and abolished Aβ toxicity to cultured cells, competing with the prevalent AChE-S protein which facilitates these processes. In vivo, double transgenic APPsw/AChE-R mice showed lower plaque burden, fewer reactive astrocytes and less dendritic damage than single APPsw mice, inverse to reported acceleration of these features in double APPsw/AChE-S mice. In hippocampi from Alzheimer's disease patients (n = 10), dentate gyrus neurons showed significantly elevated AChE-R mRNA and reduced AChE-S mRNA. However, immunoblot analyses revealed drastic reductions in the levels of intact AChE-R protein, suggesting that its selective loss in the Alzheimer's disease brain exacerbates the Aβ-induced damages and revealing a previously unforeseen linkage between cholinergic and amyloidogenic event

Protecting obfuscation against arithmetic attacks

Obfuscation, the task of compiling circuits or programs to make the internal computation unintelligible while preserving input/output functionality, has become an object of central focus in the cryptographic community. A work of Garg et al. [FOCS 2013] gave the first candidate obfuscator for general polynomial-size circuits, and led to several other works constructing candidate obfuscators. Each of these constructions is built upon another cryptographic primitive called a multilinear map, or alternatively a graded encoding scheme. Several of these candidates have been shown to achieve the strongest notion of security (virtual black-box, or VBB) against purely algebraic attacks in a model that we call the fully-restricted graded encoding model. In this model, each operation performed by an adversary is required to obey the algebraic restrictions of the graded encoding scheme. These restrictions essentially impose strong forms of homogeneity and multilinearity on the allowed polynomials. While important, the scope of the security proofs is limited by the stringency of these restrictions. We propose and analyze another variant of the Garg et al. obfuscator in a setting that imposes fewer restrictions on the adversary, which we call the arithmetic setting. This setting captures a broader class of attacks than considered in previous works. We also explore connections between notions of obfuscation security and longstanding questions in arithmetic circuit complexity. Our results include the following. (1) In the arithmetic setting where the adversary is limited to creating multilinear, but not necessarily homogenous polynomials, we obtain an unconditional proof of VBB security. This requires a substantially different analysis than previous security proofs. (2) In the arithmetic setting where the adversary can create polynomials of arbitrary degree, we show that a proof of VBB security for any currently available candidate obfuscator would imply VP != VNP. To complement this, we show that a weaker notion of security (indistinguishability obfuscation) can be achieved unconditionally in this setting, and that VBB security can be achieved under a complexity-theoretic assumption related to the Exponential Time Hypothesis

Objective selection of short-axis slices for automated quantification of left ventricular size and function by cardiovascular magnetic resonance

Background: Quantification of left ventricular (LV) volume from cardiovascular magnetic resonance images relies on subjective and often challenging selection of short-axis (SAX) slices. We hypothesized that this could be solved by defining mitral annular (MA) plane and apex in long-axis (LAX) views, which could be combined with automated LV volume analysis that does not rely on manual tracing of the endocardial border. Methods: SAX images from 50 subjects were analyzed using custom software. LV apex and insertion points of the mitral leaflets were marked on LAX views and used to approximate MA plane. End-systolic and end-diastolic LV volumes (ESV, EDV) were measured while including only slices or their parts located between MA plane and LV apex. Endocardial borders were automatically detected using our previously validated algorithm and also manually traced to obtain reference values. Results: Selection of anatomic landmarks in LAX views allowed automated measurement of LV volumes without the need for subjective slice selection. Intertechnique comparisons resulted in high correlations (EDV: r. = 0.95; ESV: r. = 0.96) and small biases (1 and 9 ml). Combined three-dimensional displays of LAX and SAX views with the MA plane showed that in 7/10 worst cases, intertechnique discordance was due to incorrect manual tracing at LV base that erroneously included part of atrial cavity in LV volume or excluded part of LV cavity, i.e., incorrect reference values. Conclusion: Defining the MA plane and apex in the LAX views obviates the need for subjective slice selection and eliminates errors in LV volume measurements

Late gadolinium enhancement cardiovascular magnetic resonance predicts clinical worsening in patients with pulmonary hypertension

<p>Abstract</p> <p>Background</p> <p>Late gadolinium enhancement (LGE) occurs at the right ventricular (RV) insertion point (RVIP) in patients with pulmonary hypertension (PH) and has been shown to correlate with cardiovascular magnetic resonance (CMR) derived RV indices. However, the prognostic role of RVIP-LGE and other CMR-derived parameters of RV function are not well established. Our aim was to evaluate the predictive value of contrast-enhanced CMR in patients with PH.</p> <p>Methods</p> <p>RV size, ejection fraction (RVEF), and the presence of RVIP-LGE were determined in 58 patients with PH referred for CMR. All patients underwent right heart catheterization, exercise testing, and N-terminal pro-brain natriuretic peptide (NT-proBNP) evaluation; results of which were included in the final analysis if performed within 4 months of the CMR study. Patients were followed for the primary endpoint of time to clinical worsening (death, decompensated right ventricular heart failure, initiation of prostacyclin, or lung transplantation).</p> <p>Results</p> <p>Overall, 40/58 (69%) of patients had RVIP-LGE. Patients with RVIP- LGE had larger right ventricular volume index, lower RVEF, and higher mean pulmonary artery pressure (mPAP), all p < 0.05. During the follow-up period of 10.2 ± 6.3 months, 19 patients reached the primary endpoint. In a univariate analysis, RVIP-LGE was a predictor for adverse outcomes (p = 0.026). In a multivariate analysis, CMR-derived RVEF was an independent predictor of clinical worsening (p = 0.036) along with well-established prognostic parameters such as exercise capacity (p = 0.010) and mPAP (p = 0.001).</p> <p>Conclusions</p> <p>The presence of RVIP-LGE in patients with PH is a marker for more advanced disease and poor prognosis. In addition, this study reveals for the first time that CMR-derived RVEF is an independent non-invasive imaging predictor of adverse outcomes in this patient population.</p

COVID-19 lockdown induced changes in NO2 levels across India observed by multi-satellite and surface observations

© Author(s) 2021. This work is distributed under the Creative Commons Attribution 4.0 License.We have estimated the spatial changes in NO 2levels over different regions of India during the COVID-19 lockdown (25 March-3 May 2020) using the satellite-based tropospheric column NO 2observed by the Ozone Monitoring Instrument (OMI) and the Tropospheric Monitoring Instrument (TROPOMI), as well as surface NO 2concentrations obtained from the Central Pollution Control Board (CPCB) monitoring network. A substantial reduction in NO 2levels was observed across India during the lockdown compared to the same period during previous business-as-usual years, except for some regions that were influenced by anomalous fires in 2020. The reduction (negative change) over the urban agglomerations was substantial (~20 %-40 %) and directly proportional to the urban size and population density. Rural regions across India also experienced lower NO 2values by ~15 %-25 %. Localised enhancements in NO 2associated with isolated emission increase scattered across India were also detected. Observed percentage changes in satellite and surface observations were consistent across most regions and cities, but the surface observations were subject to larger variability depending on their proximity to the local emission sources. Observations also indicate NO 2enhancements of up to~25%during the lockdown associated with fire emissions over the north-east of India and some parts of the central regions. In addition, the cities located near the large fire emission sources show much smaller NO 2reduction than other urban areas as the decrease at the surface was masked by enhancement in NO 2due to the transport of the fire emissions.Peer reviewedFinal Published versio

Correlation between single limb support phase and self-evaluation questionnaires in knee osteoarthritis populations

Purpose. To investigate the correlation between single limb support (SLS) phase (% of gait cycle) and the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) questionnaire and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36 Health Survey) in patients with knee osteoarthritis (OA)